Piperazine compounds for the treatment of autoimmune disease

Abstract

The present invention relates to compounds of formula (I), wherein R1 to R4 are as described herein, and their pharmaceutically acceptable salt, enantiomer or diastereomer thereof, and compositions including the compounds and methods of using the compounds.

The invention claimed is: 
     
       1. A compound of formula (I), 
       
         
           
           
               
               
           
         
         wherein: 
         R 1  is 
       
       
         
           
           
               
               
           
         
       
       wherein R 5  is cyano, C 1-6 alkoxy, C 1-6 alkyl or halogen;
 R 2  is C 1-6 alkyl; 
 R 3  is R 3a  or —COR 3b ; wherein:
 R 3a  is phenyl substituted by piperazinyl and (hydroxyC 1-6  alkyl)piperazinyl, pyridinyl substituted by piperazinyl, C 1-6 alkylpiperazinyl, 9-oxa-3,7-diaza-bicyclo[3.3.1]nonanyl, (halopyrrolidinyl)amino, (pyrrolidinylcarbonyl)piperazinyl or (((C 1-6 alkyl) 2 amino)C 1-6 alkylcarbonyl)piperazinyl, or pyrimidinyl substituted by piperazinyl or (((C 1-6 alkyl) 2 amino)C 1-6 alkylcarbonyl)piperazinyl; 
 R 3b  is 7,8-dihydro-5H-1,6-naphthyridinyl substituted by piperazinyl, 3,4-dihydro-1H-isoquinolinyl substituted by piperazinyl, isoindolinyl substituted by piperazinyl, phenylamino substituted by piperazinyl, 1,2,3,4-tetrahydroisoquinolinyl, or C 1-6  alkylpiperidinylpiperidinyl; 
 
 R 4  is C 1-6 alkyl or H; 
 or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof. 
 
     
     
       2. A compound of formula (I) according to  claim 1 ,
 wherein: 
 R 1  is 
 
       
         
           
           
               
               
           
         
       
       wherein R 5  is cyano;
 or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof. 
 
     
     
       3. A compound according to  claim 2 , wherein:
 R 2  is methyl; 
 R 3  is R 3a  or —COR 3b ; wherein:
 R 3  is R 3a  is piperazinylphenyl ; (hydroxymethyl)piperazinylphenyl; piperazinylpyridinyl; (methylpiperazinyl)pyridinyl; 9-oxa-3 , 7-diazabicyclo[3.3.1]nonanylpyridinyl; ((fluoropyrrolidinyl)amino)pyridinyl; ((pyrrolidinylcarbonyl)piperazinyl)pyridinyl; (((dimethylamino)acetyl)piperazinyl)pyridinyl; piperazinylpyrimidinyl; or ((dimethylamino)acetyl)piperazinylpyrimidinyl; 
 R 3b  is piperazinyl-7,8-dihydro-5H-1,6-naphthyridinyl; piperazinyl-3,4-dihydro-1H-isoquinolinyl; piperazinylisoindolinyl; piperazinylphenylamino; 1,2,3,4-tetrahydroisoquinolinyl; or methylpiperidinylpiperidinyl; 
 
 and 
 R 4  is methyl or H; 
 or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof. 
 
     
     
       4. A compound according to  claim 2 , or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof, wherein:
 R 3  is R 3a  or —COR 3b ;
 wherein R 3a  is pyridinyl substituted by piperazinyl; and 
 
 R 3b  is isoindolinyl substituted by piperazinyl. 
 
     
     
       5. A compound selected from:
 5-[(3R,5S)-3,5-Dimethyl-4-[(4-piperazin-1-ylphenyl)methyl]piperazin-1-yl]quinoline-8-carbonitrile; 
 4-[(3R,5R)-3,5-Dimethyl-4-[(4-piperazin-1-ylphenyl)methyl]piperazin-1-yl]quinoline-8-carbonitrile; 
 5-[(3R,5S)-3,5-Dimethyl-4-[(6-piperazin-1-yl-3-pyridyl)methyl]piperazin-1-yl]quinoline-8-carbonitrile; 
 5-[(3S,5R)-3,5-Dimethyl-4-[(5-piperazin-1-ylpyrimidin-2-yl)methyl]piperazin-1-yl]quinoline-8-carbonitrile; 
 5-[(3S,5R)-3,5-Dimethyl-4-[(5-piperazin-1-yl-2-pyridyl)methyl]piperazin-1-yl]quinoline-8-carbonitrile; 
 5-[(3S,5R)-4-[[5-[4-[2-(Dimethylamino)acetyl]piperazin-1-yl]pyrimidin-2-yl]methyl]-3,5-dimethyl-piperazin-1-yl]quinoline-8-carbonitrile; 
 5-[(3S,5R)-3,5-dimethyl-4-[[5-(4-methylpiperazin-1-yl)-2-pyridyl]methyl]piperazin-1-yl]quinoline-8-carbonitrile; 
 5-[(3S,5R)-3,5 -Dimethyl-4-[[5-(9-oxa-3,7-diazabicyclo[3.3.1]nonan-3-yl)-2-pyridyl]methyl]piperazin-1-yl]quinoline-8-carbonitrile; 
 5-[(3R,5S)-3,5 -Dimethyl-4-[[5-[[(3R,4S)-4-fluoropyrrolidin-3-yl]amino]-2-pyridyl]methyl]piperazin-1-yl]quinoline-8-carbonitrile; 
 5-[(3R,5S)-3,5 -Dimethyl-4-[[5-[4-(pyrrolidine-2-carbonyl)piperazin-1-yl]-2-pyridyl]methyl]piperazin-1-yl]quinoline-8-carbonitrile; 
 5-[(3S, 5R)-4-[[5-[4-[2-(Dimethylamino)acetyl]piperazin-1-yl]-2-pyridyl]methyl]-3,5-dimethyl-piperazin-1 -yl]quinoline-8-carbonitrile; 
 5-[(3R, 5S)-4-[[4-[2-(Hydroxymethyl)piperazin-1-yl]phenyl]methyl]-3,5-dimethyl-piperazin-1-yl]quinoline-8-carbonitrile; 
 5-[(3R,5S)-3,5-Dimethyl-4-[2-oxo-2-(2-piperazin-1-yl-7,8-dihydro-5H-1,6-naphthyridin-6-yl) ethyl]piperazin-1-yl]quinoline-8-carbonitrile; 
 5-[(3R,5S)-3,5-Dimethyl-4-[2-oxo-2-(6-piperazin-1-yl-3,4-dihydro-1H-isoquinolin-2-yl) ethyl]piperazin-1-yl]quinoline-8-carbonitrile; 
 5-[(3R,5S)-3,5-dimethyl-4-[2-oxo-2-(7-piperazin-1-yl-3,4-dihydro-1H-isoquinolin-2-yl) ethyl]piperazin-1-yl]quinoline-8-carbonitrile; 
 5-[(3R,5S)-3,5-Dimethyl-4-[2-oxo-2-(5-piperazin-1-ylisoindolin-2-yl)ethyl]piperazin-1-yl]quinoline-8-carbonitrile; 
 2-[4-(8-Cyano-5-quinolyl)-2-methyl-piperazin-1-yl]-N-(4-piperazin-1-ylphenyl)acetamide; 
 2-[4-(8-Cyano-5-quinolyl)-2-methyl-piperazin-1-yl]-N-(1,2,3,4-tetrahydroisoquinolin-6-yl) acetamide; and 
 5-[3-methyl-4-[2-[4-(1-methyl-4-piperidyl)-1-piperidyl]-2-oxo-ethyl]piperazin-1-yl]quinoline-8-carbonitrile; 
 or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof. 
 
     
     
       6. A process for the preparation of a compound of formula (I) according to  claim 1  comprising any of the following steps:
 a) coupling reaction of a compound of formula (VI), 
 
       
         
           
           
               
               
           
         
         and an amine HR 3b  in the presence of a coupling reagent and a base;
 b) carrying out a Buchwald-Hartwig amination reaction of a compound of formula (X), 
 
       
       
         
           
           
               
               
           
         
         and an amine HR 6  in the presence of a catalyst and a base; 
         wherein: 
         in step a),
 the coupling reagent, is HATU; and 
 the base, is DIPEA; 
 
         in step b), 
         the catalyst, is Ruphos Pd-G2; 
         the, is Cs2CO3; 
         X is halogen, OTf, or OMs; 
         Y is N or CH; R 6  is piperazine. 
       
     
     
       7. A pharmaceutical composition comprising a compound in accordance with  claim 1  and a therapeutically inert carrier. 
     
     
       8. A compound or pharmaceutically acceptable salt, enantiomer or diastereomer, when manufactured according to the process of  claim 6 . 
     
     
       9. A method for the treatment of systemic lupus erythematosus or lupus nephritis, which method comprises administering to a subject in need thereof a therapeutically effective amount of a compound as defined in  claim 1 . 
     
     
       10. A method for the treatment of systemic lupus erythematosus or lupus nephritis, which method comprises administering to a subject in need thereof a therapeutically effective amount of a compound as defined in  claim 5 . 
     
     
       11. A pharmaceutical composition comprising a compound in accordance with  claim 5  and a therapeutically inert carrier. 
     
     
       12. The process of  claim 6 , wherein:
 R 1  is 
 
       
         
           
           
               
               
           
         
       
       wherein R 5  is cyano;
 R 2  is C 1-6 alkyl; and 
 R 4  is C 1-6 alkyl or H. 
 
     
     
       13. The process of  claim 6 , wherein:
 R 1  is 
 
       
         
           
           
               
               
           
         
       
       wherein R 5  is cyano;
 R 2  is methyl; and 
 R 4  is methyl or H. 
 
     
     
       14. A compound according to  claim 3 , or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof, wherein:
 R 3  is R 3a  or —COR 3b ;
 wherein R 3a  is pyridinyl substituted by piperazinyl; and 
 R 3b  is isoindolinyl substituted by piperazinyl.